Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, Spain.
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.
Nat Commun. 2024 Nov 12;15(1):9515. doi: 10.1038/s41467-024-53877-z.
Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synthesis enzyme IMPDH2 is enriched on chromatin in TNBC compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent, and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response.
核代谢与 DNA 损伤反应是相互交织的过程，但精确的分子联系仍难以捉摸。在这里，我们以三阴性乳腺癌（TNBC）为模型探索这种串扰，该亚型通常容易积累 DNA 损伤。我们表明，从头嘌呤合成酶 IMPDH2 在 TNBC 中的染色质上的富集程度高于其他亚型。IMPDH2 染色质定位依赖于 DNA 损伤，并且 IMPDH2 的抑制导致 DNA 损伤的积累。在染色质上，IMPDH2 通过控制 NAD 的核可用性与 PARP1 相互作用并调节其活性，从而精细调节 DNA 损伤反应。然而，当 IMPDH2 被限制在核内时，它会耗尽核 NAD，导致 PARP1 切割和细胞死亡。我们的研究确定了 IMPDH2 的一种非典型核作用，它充当核代谢和 DNA 损伤反应的汇聚点。
